Keywords
guideline - medical oncology - pancreatic cancer treatment
Introduction
Pancreatic cancer (PC) is a relatively rare malignancy, ranking 14th in incidence
and 7th in mortality globally. In India, it ranks 24th in incidence, with 1% of new
cancer cases, and 18th in mortality, but this could have been marred by under-reporting.[1] Despite its rarity, PC is among the leading causes of cancer-related deaths worldwide,
with incidence highest in individuals aged 65 to 75 years and particularly prevalent
in Northeast India. Metastatic pancreatic cancer (MPC) has a dismal prognosis with
incidence and mortality curves running in parallel, with only 5% people surviving
at 5 years of diagnosis. Given worldwide variations in PC management (as given in
NCCN and ESMO guidelines) and diverse financial circumstances in India (government
schemes/out-of-pocket expenses), consensus recommendations suited to local needs are
essential to guide the management of PC for low- or middle-income countries.
Materials and Methods
The PC management recommendations were based on existing NCCN[2] and ESMO[3] guidelines. A panel of 39 recognized PC experts was convened to ensure a balanced
and thorough evaluation, with members voting on specific questions while abstaining
in cases of potential conflicts of interest ([Supplementary Material] [available in the online version only]). The panel discussed areas of significant
disagreement or controversy, integrating recent advances and addressing inaccuracies
before circulating the revised recommendations for further review via email. Each
recommendation follows the ESMO guideline framework,[4] including a level of evidence and grade of recommendation to indicate the strength
of the evidence and the consensus level among experts. The degree of agreement was
determined by the proportion of experts endorsing each recommendation. This meticulous
process ensures that recommendations are based on a systematic evidence review and
reflect the collective expertise of the panel. This review addresses key considerations
related to the management of PC, including diagnosis, staging, risk stratification,
treatment modalities, and palliative care.
Imaging
Multidetector computed tomography (MDCT) angiography is the gold standard for PC imaging.
The pancreatic protocol (PP) mandates intravenous iodinated contrast injection at
1.5 mL/kg at 4 to 5 mL/s with biphasic acquisitions. These include a pancreatic phase
(15–20 seconds post-trigger or 35–40 seconds post-contrast injection), which offers
maximum contrast differentiation between the hypodense lesion and pancreatic parenchyma.
A portal venous phase (30 seconds after the pancreatic phase or 65–70 seconds post-injection)
with slice thickness ≤2.5 mm aids in assessing vascular invasion and extrapancreatic
tumor spread. Furthermore, dynamic imaging during peak pancreatic and liver enhancement
phases allows for evaluating vascular invasion, extrapancreatic extension, and liver
metastases. This protocol is pivotal for preoperative therapy monitoring and posttreatment
reassessment to evaluate resectability. Submillimeter axial slices and multiplanar
reconstruction are essential, as studies demonstrate that 70 to 85% of patients can
undergo resection when MDCT confirms tumor resectability.[2]
Additionally, the accuracy of MDCT in determining resectability diminishes over time
due to the aggressive nature of PC, necessitating preoperative imaging within 4 weeks
before surgery. Usually, patients come with CT scans from outside; reimaging with
a PP is often required as these scans are suboptimal. MDCT alters management in 56%
of patients following repeat imaging.[5] Magnetic resonance imaging (MRI) is a valuable adjunct to CT in the staging of PC
whenever CT is not feasible due to contrast allergies or renal insufficiency. This
also includes instances where pancreatic tumors are inconclusive or isoattenuating,
as seen in 5 to 17% of cases. MRI also plays a critical role in characterizing pancreatic
cystic lesions, providing detailed imaging with sequences such as T2-weighted, fat-suppressed
T1-weighted, and diffusion-weighted imaging (DWI).[6] If an MRI scan is planned, it should ideally precede any interventions, such as
stent placement or biopsies, to prevent procedure-related changes, such as postintervention
pancreatitis, from obscuring diagnostic accuracy.[2] However, regardless of the abdominal imaging modality used, staging must always
include chest CT to evaluate for thoracic metastases and complete the staging workup.
Prior to surgery, liver CEMRI is recommended to exclude the presence of small liver
metastases, particularly in cases where tumor markers are elevated or CT findings
are inconclusive. MRI has also demonstrated superior sensitivity to CT for detecting
small hepatic and peritoneal metastases. Studies, including three case series and
a meta-analysis, have shown that MRI, particularly with DWI sequences, identified
liver metastases in 10 to 23% of cases that were not visible on CT. This increased
sensitivity reduces the risk of unnecessary laparotomies in patients initially deemed
operable based on CT findings.[6]
While positron emission tomography-computed tomography (PET-CT) is not routinely recommended
for the primary diagnosis of PC due to its overlap with findings from autoimmune conditions
and chronic pancreatitis, it can serve as a valuable tool in specific scenarios where
distant metastases are uncertain. For instance, PET-CT is beneficial in cases of equivocal
or indeterminate findings on standard imaging or high-risk patients with markedly
elevated CA19–9 levels, large primary tumors, or concerning symptoms such as excessive
weight loss or extreme pain. Notably, PET demonstrated a sensitivity of 61% in detecting
metastatic disease, which improves to 87% when combined with standard CT imaging,
as opposed to 57% with CT alone. Additionally, PET-CT findings have been shown to
influence clinical management, leading to changes in treatment plans in 11% of cases
with invasive PC. Moreover, in the neoadjuvant setting, PET-CT can provide valuable
information before and after initiating therapy to assess treatment response and restaging.
However, limitations include a 7.8% false-positive rate and a 9.8% false-negative
rate, as demonstrated in a meta-analysis of 17 clinical studies involving 1,343 patients.[7] Thus, while PET-CT should not replace high-quality contrast-enhanced CT, it remains
a useful adjunct in select cases where metastatic disease is suspected but not confirmed.
Before initiating chemotherapy for localized PC, cytologic or biopsy confirmation
is mandatory to establish a definitive diagnosis.[2] Fibroblast activation protein inhibitor (FAPI) PET imaging shows a promising emerging
role in staging workup. It can effectively detect small lesions due to its capability
of detecting tumors with strong desmoplastic reactions and higher tumor-to-background
contrast, resulting in superior sensitivity and positive predictive value compared
with FDG-PET/CT. Notably, FAPI-PET improved TNM staging in 25% of PC patients and
altered clinical management in 12% of cases[7] ([Table 1]).
Table 1
Imaging
|
Guidelines
|
Level of evidence
|
Grade of recommendation
|
Consensus
|
|
Statement 1
|
|
Utilize multiphasic contrast-enhanced CT for initial imaging of suspected pancreatic
cancer, incorporating late arterial and portal venous phases. If obstructive head
pancreatic cancer is causing jaundice, perform imaging prior to biliary drainage or
stenting. CT of the chest is to be done to complete the initial staging
|
III
|
A
|
35/35
|
|
Statement 2
|
|
Abdominal MRI may be considered when CT is not feasible, yields inconclusive findings,
or for the evaluation of pancreatic cystic lesions; in such instances, chest CT is
preferable for staging
|
IV
|
C
|
37/38
|
|
Statement 3
|
|
Before surgery, CEMRI of the liver may be considered to verify the absence of small
liver metastases in case of equivocal findings on CT
|
III
|
B
|
9/13
|
|
Statement 4
|
|
While PET-CT is not recommended for initial tumor diagnosis, it can be beneficial
in situations where the presence of distant metastases is uncertain, such as doubtful
initial imaging or elevated CA19-9 levels despite biliary drainage
|
III
|
C
|
32/35
|
Tissue Diagnosis
EUS-FNA is preferred due to its high accuracy and reliability in determining malignancy,
with sensitivity and specificity values of 90.8 and 96.5%, respectively. This approach
is essential for patients with neoadjuvant therapy or those with locally advanced,
borderline resectable, or metastatic PC. If EUS-FNA is not feasible, alternatives
like endoscopic cholangioscopy, percutaneous or laparoscopic biopsies, or pancreatic
ductal brushings may be used. If malignancy is unconfirmed, repeat biopsy is recommended,
with EUS-FNA and core needle biopsy at a high-volume center preferred. For borderline
resectable cases, advanced evaluation at specialized centers is advised. Surgery may
proceed without biopsy in localized PC with R0 resection potential if clinical and
radiographic findings strongly support PC, as biopsy is not mandatory. A nondiagnostic
biopsy should not delay surgical intervention when clinical suspicion of malignancy
is high. In such cases, multidisciplinary tumor board (MDTB) discussion is critical
in diagnostic and surgical management decisions. In instances where tissue diagnosis
is unavailable, serum IgG4 levels may aid in distinguishing type-I autoimmune pancreatitis
from PC.[8] Transabdominal core needle biopsy is generally not recommended unless EUS-FNA is
unavailable or not feasible. EUS-FNA is the preferred method in patients with resectable
pancreatic disease due to its superior diagnostic yield, safety profile, and significantly
reduced risk of peritoneal seeding. Unlike transabdominal approaches, EUS-FNA minimizes
the need to traverse vascular and bowel structures, lowering bleeding and infection
risks. Moreover, EUS-FNA provides critical staging information during the biopsy procedure,
which is vital for treatment planning and prognostication.
CA19–9 is a biomarker frequently expressed and shed in pancreatic and hepatobiliary
diseases but is not tumor-specific. The sensitivity of CA19–9 ranges from 79 to 81%,
with specificity between 80 and 90% in symptomatic patients, making it useful in disease
management rather than initial screening. Due to false elevation in conditions such
as biliary obstruction, cholangitis, or inflammation, its low positive predictive
value limits its utility as a reliable screening tool. Measurement of CA19–9 levels
is most accurate when performed after biliary decompression and normalization of bilirubin.
Preoperative CA19–9 levels strongly predict resectability, with values exceeding 250
U/mL increasing the likelihood of staging laparoscopy.[9] Moreover, elevated levels above 500 IU/mL are associated with advanced pathological
stage and poor survival outcomes, warranting careful consideration before surgical
intervention. It is also critical to recognize that CA19–9 is undetectable in ∼15%
of the population with blood groups having Lewis antigen-negative phenotypes, further
limiting its diagnostic reliability. CA19–9 is a valuable prognostic marker and a
tool for monitoring treatment response, particularly in advanced PC, where its levels
are elevated in nearly 80% of patients ([Table 2]).
Table 2
Tissue diagnosis
|
Guidelines
|
Level of evidence
|
Grade of recommendation
|
Consensus
|
|
Statement 5
|
|
Prior to commencing chemotherapy for localized pancreatic cancer, it is essential
to obtain cytology or biopsy confirmation, preferably guided by EUS
|
III
|
A
|
33/33
|
|
Statement 6
|
|
It is reasonable to perform a surgical procedure without a biopsy if the tumor is
resectable and R0 resection is feasible, as suggested by the imaging findings, and
provided the facility of frozen section analysis is available
|
IV
|
C
|
35/37
|
|
Statement 7
|
|
Transabdominal core needle biopsy is not indicated unless EUS is unavailable or unfeasible
for resectable pancreatic cancer.
|
III
|
C
|
32/36
|
|
Statement 8
|
|
CA19.9 levels can be used to assess disease burden and follow disease course, but
it is not a substitute for the diagnosis of pancreatic cancer
|
III
|
A
|
38/38
|
Molecular Testing
BRCA and microsatellite instability (MSI) testing are essential in PC management,
particularly for identifying germline variants linked to hereditary cancer syndromes.
BRCA1 pathogenic or likely pathogenic (P/LP) variant rates range from 1 to 11%, and
BRCA2 rates from 0 to 17%, with higher prevalence in familial PC cases and Ashkenazi
Jewish populations (5.5–19%).[10] Recent studies report actionable BRCA1 variants at 0 to 3% and BRCA2 at 1 to 6%,
underscoring the importance of genetic testing for targeted therapies like PARP inhibitors.
BRCA1/2 P/LP variants confer a lifetime PC risk of 3% in males and 2.3% in females,
emphasizing tailored risk assessment.[11] Genetic counseling is recommended for individuals with a family history of PC, early-onset
disease (<45 years), or associated cancers, supported by tools like PancPRO.[12] Evaluation should include family history of pancreatitis, melanoma, and colorectal,
breast, ovarian, or PCs. Counseling is crucial for patients with mutations in genes
such as ATM, BRCA1/2, CDKN2A, and MLH1. Preventive strategies, including smoking cessation
and weight management, are strongly advised.[13]
[14] Comprehensive genomic profiling and next-generation sequencing facilitate the identification
of mutations and fusions, aiding personalized treatment[2] ([Table 3]).
Table 3
Molecular testing
|
Guidelines
|
Level of evidence
|
Grade of recommendation
|
Consensus
|
|
Statement 9
|
|
Germline genetic testing (particularly, HRR pathway genes like BRCA, PALB2) is recommended
in all Pancreatic Cancer patients. Genetic Counselling can be considered prior to
performing genetic tests
|
III
|
A
|
35/36
|
|
Statement 10
|
|
People with a family history of pancreatic cancer, those diagnosed at a younger age
(below 45), or those at an elevated risk should consider seeking genetic counseling
|
III
|
A
|
35/35
|
|
Statement 11
|
|
Comprehensive genomic profiling for advanced pancreatic cancer is suggested if resources
permit
|
IV
|
C
|
33/35
|
Staging and Risk Stratification
Staging and Risk Stratification
The UICC TNM 8th edition provides a standardized staging system, categorizing PC into
resectable, borderline-resectable, locally advanced, or metastatic stages, guiding
treatment planning. Staging criteria incorporate the primary tumor's size and extent
and the metastatic disease's presence and distribution. Suspicious lymph nodes are
defined by enlargement (>1 cm in the short axis) or abnormal morphology, including
hypodensity, irregular margins, or involvement of adjacent vessels. Distant metastases
are present in over half of PDAC patients at diagnosis, with liver, peritoneal cavity,
and lungs being the most commonly affected sites.[15]
PC resectability assessment is guided by anatomical criteria outlined by the NCCN
guidelines ([Table 4]) and biological or conditional factors defined by the IAP consensus. Radiographic
evaluation focuses on detecting peritoneal or hepatic metastases, assessing the patency
of key vascular structures, including the superior mesenteric vein (SMV), portal vein,
and the tumor's spatial relationship with the superior mesenteric artery (SMA), celiac
axis, and hepatic artery. Borderline-resectable tumors are those tumors where there
are sufficient proximal and distal vessels for reconstruction.[16]
[17]
Table 4
Resectability criteria in pancreatic cancer (NCCN criteria)[2]
|
Arterial
|
Venous
|
|
Resectable
|
|
SMA, CA, CHA: no arterial tumor contact
|
SMV/PV: no tumor contact, or contact of <180° without vein contour irregularity
|
|
Borderline resectable (BRPC)
|
|
BR-PV (SMV/PV invasion alone)
|
|
SMV/PV: solid tumor contact of 180° or more, contact of less than 180° with contour irregularity
of the vein or thrombosis of the vein, but with suitable vessel proximal and distal
to the site of involvement, allowing for safe and complete resection and vein reconstruction.
IVC: solid tumor contact
|
|
BR-A (arterial invasion)
|
Pancreatic head/uncinate process:
SMA: solid tumor contact of <180°
CHA: solid tumor contact without extension to CA/hepatic artery bifurcation, allowing
for safe and complete resection and reconstruction. Presence of variant arterial anatomy
(RHA, CHA) and the presence of tumor contact, as it may affect surgical planning
Pancreatic body/tail:
CA: solid tumor contact of < 180°
CA: solid tumor contact of 180° or more without involvement of the aorta and with intact
and uninvolved GDA
|
|
|
Unresectable
|
|
UR-LR (locally advanced) (LAPC)
|
Head/uncinate process:
SMA, CA: solid tumor contact of 180° or more
Solid tumor contact with the 1st jejunal SMA branch
Body and tail
SMA, CA: solid tumor contact of 180° or more
Solid tumor contact with the CA and aortic involvement
|
Head/uncinate process:
SMV/PV: unreconstructible due to tumor involvement/occlusion
Contact with the most proximal draining jejunal branch into the SMV
Body and tail:
SMV/PV: unreconstructible due to tumor involvement/occlusion
|
|
UR-M (metastatic)
|
Distant metastasis (including nonregional lymph node metastasis)
|
Abbreviations: SMV, superior mesenteric vein; CA, celiac artery; CHA, common hepatic
artery; GDA, gastroduodenal artery; IVC, inferior vena cava; LR, locally advanced;
PV, portal vein; RHA, right hepatic artery; SMA, superior mesenteric artery.
The integration of biological factors such as serum CA 19–9 levels is critical for
predicting metastatic risk or recurrence. Elevated CA 19–9 levels above 500 U/mL often
signal hidden metastatic disease, necessitating a detailed preoperative evaluation.[18]
[19] Conditional factors focus on patient fitness for major surgery, assessing comorbidities,
nutritional status, and functional reserve. Additionally, responses to neoadjuvant
therapy, such as reduced tumor size or vascular encasement and normalized CA 19–9
levels, may reclassify borderline-resectable or unresectable cases as potentially
resectable.[19]
A multidisciplinary tumor board (MDTB) involving specialists in imaging, surgery,
oncology, and gastroenterology is pivotal in managing PC, influencing diagnosis and
treatment strategies.[20] MDTB decisions have been shown to alter treatment plans in 18.3% of cases. The cornerstone
of managing a patient with newly diagnosed PC is the integration of a multidisciplinary
team approach. Endoscopic biliary drainage is advised for patients with resectable
or borderline resectable disease presenting with cholangitis, undergoing neoadjuvant
therapy, or facing treatment delays exceeding 2 weeks, especially when bilirubin levels
exceed 250 µmol/L (∼15 mg/dL) or in cases of nutritional compromise. A fully covered,
self-expandable metallic stent is preferred.[21]
Only one in five patients presents with resectable disease. Even in this group, 5-year
survival remains low at 25%, with a median survival of ∼2 years following resection
and adjuvant therapy. The most significant prognostic factors for long-term survival
include negative margin status (R0 resection), smaller tumor size, and the absence
of lymph node metastases. Nonmetastatic PC is classified into resectable, borderline
resectable (BRPC), and locally advanced (LAPC) categories ([Table 4]). Resectability status should be determined through a consensus at an MDTB, considering
imaging findings, serum CA 19–9 levels, performance status, and clinical response.[22] A pooled analysis of 17 studies involving 2,242 patients demonstrated that a >50%
reduction or normalization of CA 19–9 levels following neoadjuvant therapy was significantly
associated with improved OS (p < 0.0001).[23]
The recent international consensus on BRPC defines it across three dimensions[24]:
-
Anatomical (A): Tumors with a high risk of margin-positive resection (R1 or R2).
-
Biological (B): Indicators suggestive of, but not definitive for, extrapancreatic metastatic disease,
such as elevated serum CA 19–9 or suspected metastases on imaging.
-
Conditional (C): Increased surgical risk due to host-related factors, including poor performance status
and significant comorbidities.
A systematic review and meta-analysis concluded that chronological age is not a contraindication
for resection in experienced centers. However, in patients with severe comorbidities
(ECOG PS >2) or refractory malnutrition, avoiding surgery may be warranted despite
technical feasibility.[25] Hence, the decision to proceed with surgical resection for PC should consider not
only anatomical criteria but also the tumor's biological behavior and the patient's
ability to tolerate the physiological demands of surgery ([Table 5]).
Table 5
Staging and risk stratification
|
Guidelines
|
Level of evidence
|
Grade of recommendation
|
Consensus
|
|
Statement 12
|
|
Utilize the UICC TNM 8th edition staging system for the staging of pancreatic cancer.
All pancreatic adenocarcinomas should be classified as resectable, borderline-resectable,
locally advanced, or metastatic
|
III
|
A
|
34/34
|
|
Statement 13
|
|
Assessment of resectability can be conducted through the application of both anatomical
NCCN (National Comprehensive Cancer Network) criteria or biological and conditional
features as outlined by the IAP (International Association of Pancreatology) consensus
|
III
|
A
|
38/38
|
|
Statement 14
|
|
For individuals with localized disease, it is preferable to have their imaging assessed
at a multidisciplinary tumor board (MDTB) comprising experts in pancreas imaging,
pancreas surgery, medical/radiation oncology, and gastroenterology
|
III
|
A
|
36/36
|
Resectable Pancreatic Cancer
Resectable Pancreatic Cancer
Research suggests that ∼80% of patients with localized PC exhibit micrometastases
at the time of diagnosis, as reflected by the high recurrence rates observed even
among those undergoing cancer therapy.[26]
[27] Can neoadjuvant therapy before surgery lead to better oncologic outcomes compared
with upfront surgery followed by adjuvant chemotherapy? The phase II NORPACT-1 trial
evaluated whether neoadjuvant therapy improves outcomes compared with upfront surgery
in resectable PC. A total of 140 patients were randomized to receive 4 cycles of neoadjuvant
FOLFIRINOX followed by surgery and adjuvant therapy or upfront surgery followed by
12 cycles of adjuvant FOLFIRINOX. Median overall survival (mOS) was 25.1 months in
the neoadjuvant group versus 38.5 months in the upfront surgery group, suggesting
a detrimental effect of neoadjuvant therapy. However, several limitations need to
be considered that might have influenced the outcomes. The study exclusively included
patients with tumors located in the pancreatic head and excluded patients with tumors
in the body and tail. Also, the patients in the neoadjuvant arm often required biliary
drainage and diagnostic confirmation, delaying treatment initiation by almost 2 weeks,
unlike those in the upfront surgery arm.[28] A meta-analysis of trials, including PACT-15, PREP-02/JSAP-05, PREOPANC, and NEONAX,
demonstrated that neoadjuvant chemotherapy or chemoradiation improves R0 resection
rates by 20% but does not significantly improve DFS or OS in resectable PC.[29] Hence, neoadjuvant treatment for resectable PC is not recommended outside the clinical
trial setting.
Surgical treatment for PC includes procedures such as pancreaticoduodenectomy, distal
pancreatectomy with splenectomy, or total pancreatectomy, depending on tumor location
and the extent of pancreatic involvement.[30] Patients with tumors located in the head of the pancreas typically undergo a pancreatoduodenectomy
(Whipple procedure). To achieve optimal medial clearance and enhance the likelihood
of an R0 resection, dissection of the right hemi-circumference of the SMA up to the
right side of the celiac trunk is recommended.[31] In cases of venous involvement, complete resection of the portal vein or SMV, followed
by reconstruction, can be performed to achieve an R0 resection. However, venous or
arterial resections are associated with a lower likelihood of attaining R0 margins
and reduced survival outcomes, likely reflecting the intrinsic aggressiveness of the
tumor.[32] An R1 resection is defined as microscopic tumor involvement within 1 mm of the resection
margin.[33] The following margins, when applicable, must be clearly identified: anterior, posterior,
medial (superior mesenteric groove), SMA, pancreatic transection, bile duct, and enteric
margins. For tumors in the body or tail of the pancreas, distal pancreatectomy with
splenectomy is typically performed. Radical anterograde modular pancreatosplenectomy,
involving dissection of the left hemicircumference of the SMA to the left of the celiac
trunk, improves the likelihood of R0 resection.[34]
While minimally invasive techniques may reduce morbidity, data on their oncologic
outcomes remain limited, making open surgery the standard of care.[35] Minimally invasive techniques, such as laparoscopic distal pancreatectomy, have
shown equivalent survival outcomes to open surgery, with additional benefits of shorter
hospital stays and faster recovery, as supported by the LEOPARD-1 trial.[36] Conversely, laparoscopic pancreaticoduodenectomy is technically demanding, with
high morbidity rates leading to the premature termination of the LEOPARD-2 trial,
highlighting its limited feasibility in general practice.[37]
Standard lymphadenectomy should include the excision of at least 16 lymph nodes, requiring
the removal of lymph node stations 5, 6, 8a, 12b1, 12b2, 12c, 13a, 13b, 14a, 14b,
17a, and 17b.[38] The survival benefit of extended resections, including wide para-aortic lymphadenectomy,
nerve plexus excision, and multivisceral resections, lacks robust high-level evidence.
Consequently, these procedures are not routinely recommended, as they may significantly
impair quality of life, potentially causing complications such as intractable diarrhea.
Postoperatively, reconstruction involves restoring pancreatic, biliary, and gastric
continuity. Clinically relevant postoperative pancreatic fistula remains the most
significant complication, with pancreaticojejunostomy and pancreaticogastrostomy being
commonly employed for pancreatico-enteric anastomosis, though neither has demonstrated
clear superiority.
However, in highly selected patients with stable or nonprogressive disease after neoadjuvant
therapy, these procedures may offer survival benefits over palliative care. Similarly,
radical surgery for oligometastatic disease has shown potential advantages in select
cases. The SMA-first approach, involving six distinct variations, has been proposed
to improve margin positivity in borderline resectable PC, with systematic reviews
reporting reduced blood loss and transfusion needs. A literature review identified
six surgical techniques described as “artery first,” each offering a distinct route
to the SMA: via the retroperitoneum (posterior approach), the uncinate process (medial
uncinate approach), the infracolic region medial to the duodenojejunal flexure (inferior
infracolic/mesenteric approach), the infracolic retroperitoneum lateral to the duodenojejunal
flexure (left posterior approach), the supracolic region (inferior supracolic approach),
and through the lesser sac (superior approach). These six strategies allow early assessment
of arterial involvement based on tumor size and location, before a definitive commitment
to resection. Whether their use translates into higher rates of negative surgical
margins, better locoregional control, or improved long-term survival remains to be
determined. For BRPC and LAPC, arterial resection after induction therapy is generally
not recommended but may be considered. The most common procedure involves resection
of the common or proper hepatic artery with direct or graft reconstruction. En bloc
resection of the common hepatic artery and celiac axis during distal pancreatectomy
is feasible without reconstruction.[39] Resection and reconstruction of the SMA are occasionally performed when required
for radical tumor removal.[40] Patients with PC are at significantly elevated risk for venous thromboembolic events.
Therefore, perioperative thromboprophylaxis with either unfractionated heparin or
low-molecular-weight heparin is recommended for surgical patients unless contraindications
are present.[41]
Among patients who undergo surgical resection for PC, the majority experience recurrence,
with ∼15% developing local recurrence and around 65% presenting with distant recurrence.[42] There is a universal consensus among expert groups on the necessity of adjuvant
treatment for all stages of resected PC. However, variations in practice exist across
continents. In Europe, adjuvant chemotherapy alone is the standard approach, whereas
in the United States, a combination of chemoradiotherapy (CRT) and chemotherapy is
more commonly utilized.[43]
The role of adjuvant radiotherapy or CRT remains controversial, with potential benefits
observed in margin-positive and node-positive patients. Conflicting evidence exists
from various trials. In Europe and Japan, chemotherapy alone is preferred, guided
by data from the CONKO-001, EORTC, and ESPAC-1 trials. The EORTC trial showed minimal
benefit from adding radiotherapy, while the ESPAC-1 trial suggested it might be detrimental.
In contrast, American practice often includes radiotherapy, particularly for node-positive
and margin-positive cases, drawing on findings from the GITSG and EORTC trials, along
with criticisms of the ESPAC-1 methodology. Even meta-analyses have failed to resolve
this ongoing debate on the optimal adjuvant approach.[44]
The ESPAC-1 trial first demonstrated a survival benefit from adjuvant chemotherapy
in resected PC, despite some criticism. Building on it, a German phase III trial (CONKO-1),
involving 364 patients, established the superiority of adjuvant chemotherapy with
gemcitabine over surgery alone in patients with resected PC, irrespective of the achievement
of tumor-free resection margins. An updated analysis of this trial revealed a marked
improvement in 5-year OS, which was 21% in the gemcitabine group compared with 10%
in the surgery-alone group.[45] Subsequently, the ESPAC-3 trial showed comparable survival benefits with adjuvant
gemcitabine or 5-fluorouracil (5-FU) plus leucovorin.[46]
The ESPAC-4 trial, a large Phase III study involving 732 patients, compared adjuvant
gemcitabine monotherapy with a combination regimen of gemcitabine and capecitabine
(GemCap). The study demonstrated a modest improvement in survival outcomes with the
combination therapy. The mOS was 28.0 months for the combination group versus 25.5
months for the gemcitabine-alone group (p = 0.032). Additionally, the 5-year OS rate was 29% with the combination therapy,
compared with 16% with gemcitabine alone.[47]
The Phase III PRODIGE-24 trial represents a landmark study in the treatment of resected
PC, comparing 6 months of adjuvant FOLFIRINOX (a combination of fluorouracil, leucovorin,
irinotecan, and oxaliplatin) to gemcitabine monotherapy. The trial demonstrated a
significant improvement in median disease-free survival (DFS), with FOLFIRINOX achieving
21.6 months compared with 12.8 months. This translated into a notable mOS benefit,
extending from 35 to 54 months, with a 3-year OS of 63 versus 49%. This represents
the longest median survival reported in a Phase III trial of adjuvant therapy for
PC and has established FOLFIRINOX as the standard of care for patients with resected
PC who are fit for this regimen.[48] These findings have established mFOLFIRINOX as the preferred adjuvant chemotherapy
regimen for patients with good performance status. In a recent ESPAC4 update at 104
months, 732 patients were randomized to gemcitabine (n = 367) or GemCap (n = 365). mOS was 29.5 months with gemcitabine versus 31.6 months with GemCap (p = 0.031). In R0 patients, mOS was 32.2 months on gemcitabine versus 49.9 months on
GemCap (p = 0.002). Lymph node–negative patients had a higher 5-year OS with GemCap (59%) than
with gemcitabine (53%; p = 0.04). Among PRODIGE24-ineligible patients (n = 193), GemCap also improved survival (25.9 vs. 20.7 months; p = 0.038). GemCap remains a standard option for those ineligible for mFOLFIRINOX,
with particular benefit in R0 and lymph node–negative disease.[49]
The recent Phase III APACT (Adjuvant Therapy for Patients with Resected Pancreatic
Cancer) trial evaluated gemcitabine alone versus gemcitabine combined with nab-paclitaxel
in the adjuvant setting. While the study did not achieve its primary endpoint of improved
mDFS and hence gemcitabine and nab-paclitaxel (GN) is not a recommended regimen for
adjuvant therapy.[50] Regular follow-up after curative-intent treatment is encouraged despite the evidence
being limited regarding its impact. Although active surveillance may detect recurrence
earlier and facilitate treatment, the effect on OS is still uncertain[51] ([Table 6]).
Table 6
Resectable pancreatic cancer
|
Guidelines
|
Level of evidence
|
Grade of recommendation
|
Consensus
|
|
Statement 15
|
|
Surgical patients should be provided with perioperative thromboprophylaxis, using
either unfractionated heparin or low-molecular-weight heparin unless otherwise contraindicated
|
I
|
A
|
28/35
|
|
Statement 16
|
|
Endoscopic biliary drainage is advisable for patients with cholangitis or those scheduled
for neoadjuvant treatment or those facing any inordinate delay exceeding 2 weeks when
the bilirubin level exceeds 250 mmol/L (∼15 mg/dL) or if they are nutritionally compromised.
Placement of a fully covered, self-expandable metallic biliary stent is preferred
for resectable and borderline resectable disease; the stent should be a “short SEMS”
|
I
|
A
|
35/36
|
|
Statement 17
|
|
The use of neoadjuvant therapy is not advised for resectable pancreatic cancer, primarily
due to the limited availability of phase III evidence, unless within the framework
of clinical trials. However, it may be considered in cases of equivocal imaging or
elevated tumor markers
|
II
|
B
|
34/36
|
|
Statement 18
|
|
For patients with tumors in the body of the pancreas, it is recommended to undergo
radical anterograde modular pancreato-splenectomy, including dissection of the SMA
to the left of the coeliac trunk
|
IV
|
B
|
25/26
|
|
Statement 19
|
|
A standard lymphadenectomy, involving the removal of 16 lymph nodes, is advised for
adequate pathological staging. Pathological analysis should report the total number
of examined lymph nodes and the lymph node ratio. Additionally, frozen section analysis
of pancreatic neck transection and common bile duct transection margins for a minimum
of 4 mm is suggested
|
IV
|
B
|
36/36
|
|
Statement 20
|
|
Adjuvant chemotherapy for 6 months is recommended for all patients
|
I
|
A
|
37/37
|
|
Statement 21
|
|
mFOLFIRINOX should be a preferred option for adjuvant therapy for patients with ECOG
PS 0 or 1
|
I
|
A
|
39/39
|
|
Statement 22
|
|
Gemcitabine with or without capecitabine is an acceptable alternative for patients
unfit for mFOLFIRINOX
|
I
|
B
|
39/39
|
|
Statement 23
|
|
Gemcitabine and nab-paclitaxel are not recommended for adjuvant therapy in resected
pancreatic cancer
|
II
|
B
|
32/33
|
|
Statement 24
|
|
Adjuvant radiotherapy may be considered on an individual patient basis if the resection
margins are positive
|
I
|
B
|
34/37
|
|
Statement 25
|
|
Regular follow-up is recommended for patients who have undergone resection for pancreatic
cancer, even though there is insufficient evidence demonstrating an impact on overall
survival
|
IV
|
B
|
35/36
|
Borderline Resectable Pancreatic Cancer
Borderline Resectable Pancreatic Cancer
Evidence supporting neoadjuvant therapy remains limited, with literature-based meta-analyses
comparing it to upfront surgery followed by adjuvant chemotherapy yielding conflicting
results regarding R0 resection rates and potential survival benefits.[52]
[53] The benefit of adjuvant chemotherapy following neoadjuvant therapy and pancreatectomy
has yet to be determined, as randomized trial data addressing this question are currently
unavailable. Several recent trials, including Southwest Oncology Group (SWOG) 1505,
PREOPANC, A021501, and ESPAC-5F, have provided valuable insights into the role of
neoadjuvant therapy in this context.[54]
[55]
[56]
[57]
In borderline resectable PC, the SWOG 1505 trial comparing perioperative mFOLFIRINOX
with GN found no significant differences in outcomes among patients who underwent
surgery (72%) or in median survival.[55] The primary endpoint of achieving a 2-year survival rate of 58% was not met. Notably,
the trial highlighted the critical importance of evaluating patients at high-volume
centers within a multidisciplinary setting, as nearly one-third of patients initially
classified as having resectable disease were determined to be unresectable upon central
review.
The ESPAC-5F trial, presented at the ASCO 2020 Annual Meeting, evaluated surgery alone
versus several perioperative regimens (CRT, mFOLFIRINOX, and gemcitabine plus capecitabine)
in patients with borderline resectable PC. Approximately two-thirds of patients in
all arms underwent primary tumor resection. R0 resection rates were significantly
higher with CRT (37 vs. 14% for surgery alone), and 1-year OS was improved in all
neoadjuvant arms compared with the surgery-alone arm (77 vs. 42%). Among the neoadjuvant
strategies, mFOLFIRINOX achieved the highest 12-month OS (84%), although the trial
was not powered for direct comparisons between neoadjuvant regimens.[56]
The Dutch PREOPANC study provides additional evidence supporting neoadjuvant CRT for
patients with resectable or borderline resectable PC. While the resection rate was
high in the upfront surgery group, the R0 resection rate was significantly higher
in the neoadjuvant therapy group (71 vs. 40%). Additionally, among patients who underwent
surgery, the NACT arm demonstrated improved OS (35 vs. 20 months; p = 0 0.029).[57] This study questions the benefit of adding radiotherapy to neoadjuvant chemotherapy.
PREOPANC reported a 5-year OS of 20.5% with NACRT versus 6.5% with upfront surgery;
notably, the OS in the control arm fell below the historical landmark of 10%.[45] Given the relatively young, good-performance-status population with more than half
of the patients having resectable tumors in this study, as well as the conflicting
data related to the correlation between R0 resection and improvement in OS, the role
of radiotherapy in the neoadjuvant setting remains unsubstantiated. The results of
the ALLIANCE A021806 study are eagerly awaited. This randomized trial aims to assess
the efficacy of perioperative FOLFIRINOX compared with upfront surgical resection
followed by adjuvant FOLFIRINOX.[58]
The benefit of adding radiation therapy in R1 resection to improve local control in
a disease often marked by systemic failure remains debated. ESPAC-1 showed no survival
advantage with adjuvant radiation added to chemotherapy, regardless of margin status.[59] However, prospective and retrospective analyses, including over 1,200 patients,
demonstrated improved outcomes with adjuvant chemoradiation, particularly in the R1
subset.[60] A meta-analysis of four RCTs further supported greater survival benefit in R1 over
R0 resections.[61] Hence, adjuvant radiotherapy in addition to chemotherapy may be considered on the
basis of the individual patient if the resection margins are positive. Radiation therapy
in PC is typically administered concurrently with gemcitabine- or fluoropyrimidine-based
chemotherapy. Retrospective analyses showed improved outcomes with hypofractionated
or stereotactic body radiotherapy (SBRT) over conventionally fractionated RT, including
better mOS (13.9 vs. 11.6 months; p < 0.001) and 2-year OS (21.7 vs. 16.5%; p = 0.001)[62] ([Table 7]).
Table 7
Borderline resectable pancreatic cancer (BRPC)
|
Guidelines
|
Level of evidence
|
Grade of recommendation
|
Consensus
|
|
Statement 26
|
|
Neoadjuvant strategy is recommended in all patients with BRPC due to the high risk
of R1/R2 resection and potential survival advantage
|
II
|
A
|
39/39
|
|
Statement 27
|
|
Duration of 3–6 months of neoadjuvant therapy is recommended before proceeding to
surgery; the exact duration can be decided on an individual case-by-case basis
|
IV
|
B
|
37/37
|
|
Statement 28
|
|
mFOLFIRINOX or gemcitabine with nab-paclitaxel are both acceptable systemic therapy
options for neoadjuvant setting. GEM-CIS can be used in cases of germline BRCA mutation
|
III
|
A
|
36/36
|
|
Statement 29
|
|
Moderately hypofractionated radiation therapy or SBRT may be considered on individual
patient basis before surgical exploration
|
III
|
C
|
29/35
|
|
Statement 30
|
|
Surgically eligible patients displaying no disease progression radiologically and
a decrease in CA 19-9 following neoadjuvant therapy should undergo exploration, unless
contraindicated
|
III
|
C
|
33/36
|
Locally Advanced Pancreatic Cancer
Locally Advanced Pancreatic Cancer
For patients with locally advanced, unresectable PC, an initial 6-month course of
systemic combination chemotherapy is recommended. In case of absence of disease progression
following induction therapy, the addition of CRT may be considered.[63] As with resectable disease, the role of CRT in locally advanced unresectable PC
remains debated. The international Phase III LAP07 trial evaluated gemcitabine with
or without erlotinib, followed by a second randomization for patients with at least
stable disease after 4 months to either continue chemotherapy or transition to CRT
with capecitabine as a radiation sensitizer. The trial was terminated at its first
planned interim analysis due to a lack of efficacy, showing no improvement in OS or
PFS with consolidative CRT. However, a subsequent analysis revealed that patients
receiving radiation therapy experienced significantly lower rates of local tumor progression
(34 vs. 65%; p < 0.0001) and a longer interval before reinitiation of chemotherapy (159 vs. 96 days;
p = 0 0.05).[64]
The NEOLAP trial recently compared a continuous regimen of GN with a sequential approach
involving GN followed by FOLFIRINOX. Approximately two-thirds of patients in both
arms proceeded to surgery, with no significant differences observed in R0 resection
rates or mOS.[54] In the NRG-RTOG 0848 step 2 randomization (n = 354), at a median follow-up of 2.2 years, adjuvant fluoropyrimidine plus radiotherapy
improved DFS across all patients, with additional DFS and OS benefit in node-negative
disease. Five-year OS for node-negative patients was 48% (chemo + CRT) versus 29%
(chemo), while node-positive patients showed no OS improvement. Overall, 5-year DFS
was 21% (chemo + CRT) versus 15% (chemo) with similar grade 4–5 adverse events. This
study suggests that the addition of RT might benefit a particular subset of population.[65]
A study on chemo-naive advanced PC patients aged >65 years with ECOG PS <2 evaluated
a modified biweekly regimen of gemcitabine (1,000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1 and 15 of a 28-day cycle. Among 73 elderly patients, mOS and PFS were
9.1 and 4.8 months, respectively. This regimen demonstrated efficacy comparable to
MPACT historical controls, with fewer dose reductions, lower costs, and a favorable
toxicity profile.[66] Upon completing planned chemotherapy, patients should undergo reevaluation by a
multidisciplinary team with extensive expertise in PC. This assessment determines
potential eligibility for surgical resection. For those deemed potentially resectable,
consideration should be given to incorporating CRT ([Table 8]).
Table 8
Locally advanced pancreatic cancer (LAPC)
|
Guidelines
|
Level of evidence
|
Grade of recommendation
|
Consensus
|
|
Statement 31
|
|
All patients should receive chemotherapy for at least 6 months before evaluating for
potential resectability/conversion. The preferred regimen is mFOLFIRINOX; however,
gemcitabine and nab-paclitaxel is an acceptable option
|
I
|
A
|
35/35
|
|
Statement 32
|
|
Consideration for resection exploration may arise in the presence of a substantial
CA19-9 level decrease, clinical improvement, and tumor downstaging. While arterial
resection post-induction therapy is generally not recommended, experienced centers
may contemplate it on a case-by-case basis for selected patients
|
IV
|
C
|
35/35
|
|
Statement 33
|
|
Patients not undergoing surgery after systemic therapy may be considered for consolidated
RT
|
IV
|
C
|
33/36
|
Metastatic Pancreatic Cancer
Metastatic Pancreatic Cancer
The insidious progression and nonspecific clinical manifestations of PC often lead
to delayed diagnosis.[67] The molecular heterogeneity of PC, combined with the desmoplastic and immunosuppressive
characteristics of its tumor microenvironment, significantly limits the efficacy of
treatment options for patients with MPC. To date, conventional chemotherapy remains
the cornerstone of treatment, offering the primary means of improving survival outcomes
in patients with MPC.[68]
A pivotal clinical trial published in 1997 compared gemcitabine versus fluorouracil,
demonstrating median survival durations of 4.4 months in the fluorouracil group and
5.7 months in the gemcitabine group. Following these results, gemcitabine was established
as the standard of care for chemotherapy in this setting.[69] Subsequent studies explored various doublet combinations with gemcitabine, including
cisplatin,[70] 5-FU,[71] and capecitabine,[72] yielding only modest benefits. The emergence of triplet regimens ultimately established
the standard of care.
The phase III ACCORD-11 trial showed that FOLFIRINOX significantly outperformed gemcitabine
in treating MPC in patients younger than 75 years. The regimen achieved higher response
rates, progression-free survival, and OS with a median survival of 11.1 months versus
6.8 months for gemcitabine (p < 0.001).[73] While FOLFIRINOX offers significant clinical benefits, it is associated with a higher
incidence of febrile neutropenia, sensory neuropathy, and gastrointestinal toxicities.
Consequently, this regimen is recommended primarily for patients aged 75 years or
younger with good performance status and no substantial risk of cholestasis or cholangitis.
The phase III MPACT trial demonstrated that GN combination therapy outperformed gemcitabine
alone as a first-line treatment for MPC. Among 861 patients (ECOG 0–2), mOS was 8.5
months with the addition of nab-paclitaxel versus 6.7 months with gemcitabine alone
(p < 0.001). Additionally, the adverse effects associated with this regimen appear to
be less severe than those observed with FOLFIRINOX, making it a suitable option for
a broader patient population.[74] Based on the current evidence, FOLFIRINOX and GN are the preferred treatment regimens
for patients with good performance status. Retrospective studies suggest FOLFIRINOX
shows greater activity and is often used in fit patients with better ECOG PS. However,
a meta-analysis of 3,813 patients found no significant OS or PFS advantage over GN
as first-line therapy for MPC.[75]
Gemcitabine combined with erlotinib may be a viable alternative.[76] For patients with ECOG PS 2 or significant comorbidities, other acceptable first-line
therapies include single-agent gemcitabine, 5-FU/capecitabine, FOLFOX, or gemcitabine–capecitabine.
Where available, S-1 monotherapy offers a convenient oral alternative to gemcitabine.
The NAPOLI-3 trial compared NALIRIFOX (liposomal irinotecan, 5-FU, and oxaliplatin)
with nab-paclitaxel and gemcitabine in 770 de novo MPC patients. NALIRIFOX demonstrated
superior mOS (11.1 vs. 9.2 months, p = 0.036). Based on these results, the FDA approved NALIRIFOX as a first-line treatment
for metastatic pancreatic adenocarcinoma.[77] The SEQUENCE trial evaluated sequential GN followed by mFOLFOX versus GN as first-line
therapy for MPC. The sequential regimen significantly improved mOS (13.2 vs. 9.7 months)
and median PFS (mPFS; 7.9 vs. 5.2 months) compared with standard therapy.
Less than half of the patients with advanced PC receive second-line therapy.[78] Second-line therapy selection depends on ECOG PS, comorbidities, and organ function.
Most studies in this setting, conducted pre-FOLFIRINOX, assessed oxaliplatin-based
chemotherapy post-gemcitabine failure, now applicable only to a small subset of patients
in the current era. The phase III NAPOLI-1 trial demonstrated improved outcomes with
nanoliposomal irinotecan plus 5-FU over 5-FU alone in MPC, with mOS of 6.1 versus
4.2 months (p = 0.012). Secondary endpoints, including PFS, objective response rates (ORRs), and
time to treatment failure, were also significantly better. Additionally, contrasting
findings on FOLFOX as a second-line regimen merit consideration. The CONKO-003 trial
reported a significant OS benefit with FOLFOX compared with 5-FU/LV monotherapy, while
the PANCREOX study did not. Differences may stem from lower oxaliplatin doses and
better tolerance in the CONKO-003 trial.[79]
[80] Following gemcitabine-based regimens, nanoliposomal irinotecan plus 5-FU is preferred.
If unavailable, 5-FU with irinotecan or oxaliplatin may be used, with the choice guided
by neuropathy status, though meta-analysis favors irinotecan combinations.[81]
In a systematic review of seven phase III trials (N = 2,581) testing first-line NALIRIFOX, FOLFIRINOX, or GN for MPC, mPFS was longer
with NALIRIFOX (7.4 months) or FOLFIRINOX (7.3 months) than with GN (5.7 months).
Similarly, mOS was lower with GN (10.4 months) compared with NALIRIFOX (11.1 months)
and FOLFIRINOX (11.7 months), while there was no statistically significant difference
in ORRs among the three regimens, with NALIRIFOX having considerably fewer grade 3
toxicities.[82] Hence, NALIRIFOX has emerged as a feasible regimen for patients ineligible for FOLFIRINOX,
particularly those requiring a triplet regimen like body or tail pancreatic tumors,
where DNA adduct accumulation augments the efficacy of platinum-based therapies.[82] Based on retrospective data, gemcitabine plus cisplatin, FOLFIRINOX, or modified
FOLFIRINOX are suitable treatment options for patients with MPC and known BRCA1/2
or PALB2 mutations, as they achieve good response to platinum-based chemotherapy regimens.[83]
Maintenance strategies are seldom utilized in PC, where mPFS ranges from 3 to 5 months
and mOS remains below 9 to 10 months, largely due to the disease's aggressive nature
and limited life expectancy. The POLO study evaluated maintenance therapy with olaparib
versus placebo in 154 patients with MPC and germline BRCA1/2 mutations who had not
progressed after ≥16 weeks of platinum-based chemotherapy. Olaparib significantly
improved mPFS (7.4 vs. 3.8 months, p = 0.004); however, final OS data showed no significant benefit (19.0 vs. 19.2 months,
p = 0.3487).[84] Olaparib is FDA-approved for this indication, yet certain limitations warrant caution.
Chemotherapy was administered for only 4 months instead of the standard 6, and 11%
of the placebo group demonstrated disease regression, suggesting sustained chemotherapy
effects. Additionally, no quality-of-life improvement was observed, and olaparib poses
significant tolerability challenges.
MSI-high (MSI-H) or mismatch repair-deficient (dMMR) PC and NTRK fusion-positive PC
are rare entities and are seen in less than 1% of cases.[85] In the phase II KEYNOTE-158 study, 22 MSI-H/dMMR PC patients treated with pembrolizumab
showed an ORR of 18% (one complete response and three partial responses), with mPFS
and mOS of 2.1 and 3.7 months, respectively.[86] Although anecdotal, dual immune checkpoint inhibition has shown promising responses.
In a study of 10 MSI-H MPC patients treated with nivolumab and ipilimumab, an ORR
of 30% (including two complete responses) and a disease control rate of 50% were observed.[87] A phase I/II study on NTRK fusion-positive tumors, including 2% PC cases, demonstrated
the promising efficacy of targeted inhibitors like larotrectinib and entrectinib,
with a 75% response rate and sustained responses.[88]
The DESTINY-PanTumor2 trial led to tumor-agnostic approval for Fam-trastuzumab deruxtecan-nxki
in HER2-positive (IHC3 + )/IHC2+ FISH-positive solid tumors, and this trial included
25 patients with MPC that showed 4% ORR and 3.2 months mPFS with T-DXd.[89] Dabrafenib–trametinib combination also has tumor-agnostic approval in BRAFV600E
mutation in solid tumors based on the NCI-MATCH platform trial that included patients
with MPC. KRAS mutations are present in almost 90% of MPC, most commonly bG12D, G12V,
and G12R, which make these mutations important targets for future therapies. However,
the KRAS12GC mutation is detected in only 2 to 3% of MPC. Sotorasib and adagrasib
have shown efficacy in the KRAS G12C mutation. In a Phase I/II trial with KRAS G12C-mutated
advanced PC, 8 of 38 patients had confirmed objective response with sotorasib.[90] A multicohort phase I/II study evaluating adagrasib showed partial responses in
50% of patients with advanced pancreatic adenocarcinoma.[91]
Less than 10% of patients with MPC present with limited metastatic spread, which might
be amenable to local ablative therapy in combination with systemic therapy. A proposed
criterion to define oligometastatic PC is characterized by (1) ≤4 liver or lung metastatic
lesions, (2) CA 19–9 levels <1,000 U/mL, and (3) response to systemic therapy.[92] The role of metastatectomy remains unclear and is recommended only for select patients,
particularly those with durable radiologic and biochemical responses and low-volume
lung-only metastases.[93] A systematic review and meta-analysis of six retrospective studies demonstrated
improved survival in patients receiving chemotherapy followed by surgery compared
with chemotherapy alone, with mOS ranging from 23 to 56 months versus 11 to 16 months,
respectively. FOLFIRINOX was the most commonly used chemotherapy regimen.[94] A single-center study involving 85 patients reported a mOS of a little over 1 year
and a 5-year survival rate of 8%.[95] Another study on 78 patients suggested prolonged mOS in lung-only metastasis treated
with surgery or stereotactic radiotherapy (67.5 months) compared with chemotherapy
alone (33.8 months) or observation (29.9 months)[96] ([Table 9]).
Table 9
Metastatic pancreatic cancer (MPC)
|
Guidelines
|
Level of evidence
|
Grade of recommendation
|
Consensus
|
|
Statement 34
|
|
mFOLFIRINOX remains the preferred systemic therapy option for newly diagnosed patients
with MPC who have ECOG PS—0 or 1
|
I
|
A
|
36/36
|
|
Statement 35
|
|
Gemcitabine and nab-paclitaxel may be an acceptable alternative for patients with
MPC who have ECOG PS > 1
|
II
|
A
|
33/34
|
|
Statement 36
|
|
For elderly and/or frail individuals, gemcitabine monotherapy can be considered
|
I
|
B
|
33/33
|
|
Statement 37
|
|
Sequential/alternating treatment with nab-GEM followed by mFOLFOX or treatment with
NALIRIFOX may be considered for some patients
|
III
|
C
|
16/27
|
|
Statement 38
|
|
For patients with BRCA mutation, platinum-based chemotherapy (mFOLFIRINOX or GEM-CIS)
is suggested
|
III
|
A
|
31/31
|
|
Statement 39
|
|
Maintenance with olaparib is suggested in patients with BRCA germline mutation who
have completed 4–6 months of induction chemotherapy and if it has not progressed
|
I
|
C
|
28/29
|
|
Statement 40
|
|
For patients with dMMR or MSI-high pancreatic cancer, immunotherapy (pembrolizumab
preferred) should be considered for second line and beyond
|
II
|
A
|
30/30
|
|
Statement 41
|
|
For patients with NTRK fusion, larotrectinib or entrectinib should be considered for
second line and beyond
|
III
|
A
|
30/30
|
Palliative Setting
Early palliative care integration is essential in MPC to address symptoms such as
pain secondary to celiac plexus involvement, jaundice from biliary obstruction, and
gastric outlet obstruction due to locoregional disease. Management includes palliative
care interventions with analgesics like morphine, palliative chemotherapy, and often
involves interventional pain management and endoscopy specialists. Although preoperative
biliary drainage is not routinely performed due to increased risk of complications,[21] it is indicated for patients presenting with cholangitis, significant comorbidities,
poor nutritional status, or deranged renal dysfunction.[97] Operative bilioenteric bypass, such as Roux-en-Y hepatico- or choledochojejunostomy,
was historically preferred for locally advanced, incurable PC. Currently, endoscopic
biliary stenting with ERCP is the standard for palliating obstructive jaundice.[98] Exercise is increasingly recognized as a therapeutic approach for mitigating fatigue,
enhancing psychological health, preserving muscle mass, improving physical function,
and maintaining quality of life in PC patients, who are predisposed to sarcopenia
and cachexia, while also potentially normalizing tumor vasculature to optimize chemotherapy
delivery and activating immune responses through the interleukin-15 (IL-15) axis.[99]
[100]
[101] Pancreatic enzyme replacement therapy, administered in divided doses during meals,
is effective in managing symptoms of exocrine insufficiency in PC patients, including
weight loss, abdominal discomfort, and steatorrhea, with initial dosing recommendations
of 30,000 to 40,000 IU per meal and 15,000 to 20,000 IU per snack along with proton
pump inhibitors as adjuncts arising due to tumor-induced parenchymal damage, ductal
obstruction, or surgical resection.[102] Discussions about various management options should include prognosis and a balanced
assessment of risks and benefits. Intensive care unit (ICU) admission is common in
the final month of life[103] and should be avoided in view of poor outcomes and financial toxicity with such
strategies. Proactive incorporation of end-of-life (EOL) care discussions facilitates
better understanding of disease trajectory for patients and caregivers and must be
part of the palliative care goals in every institution ([Table 10]).
Table 10
Palliative setting
|
Guidelines
|
Level of evidence
|
Grade of recommendation
|
Consensus
|
|
Statement 42
|
|
Preferential management of duodenal obstruction involves considering endoscopic placement
of an expandable metal stent or palliative surgical bypass whenever feasible
|
IV
|
C
|
20/22
|
|
Statement 43
|
|
It is highly advisable to have early involvement of a pain control specialist and
a nutritionist for effective pain control and expert nutritional management
|
III
|
A
|
29/30
|
|
Statement 44
|
|
Engaging in physical activity is advised as a beneficial treatment for patients to
cope with fatigue and emotional strain, to prevent muscle atrophy, to improve physical
abilities, and to sustain a good quality of life
|
III
|
A
|
27/27
|
|
Statement 45
|
|
The use of pancreatic enzyme replacement therapy is effective in alleviating symptoms
associated with exocrine insufficiency, including weight loss, abdominal discomfort,
and steatorrhea may be considered
|
III
|
A
|
26/27
|
In the context of India as a low- to middle-income country with limited resources,
the consensus guidelines emphasize cost-effective, pragmatic approaches to PC management,
prioritizing MDTBs in high-volume centers to optimize decision-making and avoid unnecessary
interventions, given prevalent out-of-pocket expenses and reliance on government schemes
like Pradhan Mantri Jan Arogya Yojana—Ayushman Bharat (PMJAY—Ayushman Bharat). For
diagnosis and staging, MDCT with PP remains the gold standard, but reimaging should
be judiciously performed only when prior scans are suboptimal, while MRI is reserved
for cases with CT contraindications or inconclusive findings to minimize costs; PET-CT
is not routine and recommended only for equivocal metastases in high-risk patients.
Tissue diagnosis via EUS-FNA is preferred at specialized centers, with alternatives
like percutaneous biopsies used when EUS is unavailable, and CA19–9 monitoring is
advocated post-biliary decompression for its prognostic value without over-reliance
due to false positives. Molecular testing for BRCA and MSI is essential for targeted
therapies like PARP inhibitors, but genetic counseling should integrate family history
assessments using accessible tools like PancPRO, focusing on high-risk groups such
as those with familial syndromes. For resectable PC, upfront surgery followed by adjuvant
chemotherapy (mFOLFIRINOX for fit patients or gemcitabine-capecitabine for others)
is standard, avoiding neoadjuvant therapy outside trials to reduce delays and costs;
in borderline resectable cases, neoadjuvant regimens like FOLFIRINOX or GN are considered,
but radiation is debated and not routinely added unless margins are positive. In locally
advanced and metastatic settings, first-line therapies prioritize FOLFIRINOX or GN
for good performance status patients, with gemcitabine monotherapy or capecitabine
for those with ECOG PS 2 or comorbidities, and second-line options like nanoliposomal
irinotecan plus 5-FU if available; maintenance olaparib is limited to germline BRCA
mutants post-platinum therapy. Early palliative care integration, including endoscopic
stenting for jaundice, analgesics for pain, pancreatic enzyme replacement for exocrine
insufficiency, and exercise for cachexia, is crucial to enhance quality of life while
avoiding aggressive end-of-life ICU admissions to mitigate financial toxicity, ensuring
equitable access through resource-stratified adaptations ([Table 11]).
Table 11
Standard-of-care systemic therapy in the management of pancreatic cancer
|
Setting
|
Treatment context
|
ECOG PS 0/1
|
ECOG PS > 1 or age > 75 y
|
Duration
|
Special considerations
|
|
Resectable pancreatic cancer
|
Adjuvant
|
mFOLFIRINOX (PRODIGE 24)[48]
|
Gemcitabine ± capecitabine (ESPAC-4)[49]
|
6 mo
|
|
|
Borderline resectable pancreatic cancer (BRPC)
|
Neoadjuvant
|
mFOLFIRINOX[56]
|
Gemcitabine + nab-paclitaxel
|
3–6 mo
|
If germline BRCA mutation: gemcitabine + cisplatin
If R1 resection: consider adjuvant radiation with gemcitabine or fluoropyrimidine-based
chemotherapy[60]
|
|
Locally advanced pancreatic cancer
|
Neoadjuvant
|
mFOLFIRINOX
|
Gemcitabine + nab-paclitaxel
|
6 mo
|
If R1 resection: consider adjuvant radiation with gemcitabine or fluoropyrimidine-based
chemotherapy[61]
|
|
Metastatic pancreatic cancer (MPC)
|
1st line
|
mFOLFIRINOX (ACCORD-11)[75] or NALIRIFOX (NAPOLI-3)[77] or sequential gemcitabine + nab-paclitaxel followed by mFOLFOX (NEOLAP)[54]
|
Gemcitabine + nab-paclitaxel (MPACT)[66]
[74]
|
If germline BRCA mutation: gemcitabine + cisplatin for 6 mo followed by maintenance
Olaparib[84]
|
|
|
MPC
|
2nd line[81]
|
|
|
|
If dMMR/MSI-H: immunotherapy (pembrolizumab preferred)[86]
If NTRK fusion: larotrectinib or entrectinib[88]
|
